ER stress increases StarD5 expression by stabilizing its mRNA and leads to relocalization of its protein from the nucleus to the membranes.

StarD5 belongs to the StarD4 subfamily of steroidogenic acute regulatory lipid transfer (START) domain proteins. In macrophages, StarD5 is found in the cytosol and maintains a loose association with the Golgi. Like StarD1 and StarD4, StarD5 is known to bind cholesterol. However, its function and regulation remain poorly defined. Recently, it has been shown that its mRNA expression is induced in response to different inducers of endoplasmic reticulum (ER) stress. However, the molecular mechanism(s) involved in the induction of StarD5 expression during ER stress is not known. Here we show that in 3T3-L1 cells, the ER stressor thapsigargin increases intracellular free cholesterol due to an increase in HMG-CoA reductase expression. Activation of StarD5 expression is mediated by the transcriptional ER stress factor XBP-1. Additionally, the induction of ER stress stabilizes the StarD5 mRNA. Furthermore, StarD5 protein is mainly localized in the nucleus, and upon ER stress, it redistributes away from the nucleus, localizing prominently to the cytosol and membranes. These results reveal the increase in StarD5 expression and protein redistribution during the cell protective phase of the ER stress, suggesting a role for StarD5 in cholesterol metabolism during the ER stress response.